Abnormal energy regulation in early life: childhood gene expression may predict subsequent chronic mountain sickness.
BACKGROUND
Life at altitude depends on adaptation to ambient hypoxia. In the Andes, susceptibility to chronic mountain sickness (CMS), a clinical condition that occurs to native highlanders or to sea level natives with prolonged residence at high altitude, remains poorly understood. We hypothesized that hypoxia-associated gene expression in children of men with CMS might identify markers that predict the development of CMS in adults. We assessed distinct patterns of gene expression of hypoxia-responsive genes in children of highland Andean men, with and without CMS.


METHODS
We compared molecular signatures in children of highland (HA) men with CMS (n = 10), without CMS (n = 10) and in sea level (SL) children (n = 20). Haemoglobin, haematocrit, and oxygen saturation were measured. Gene expression in white cells was assessed at HA and then, in the same subjects, within one hour of arrival at sea level.


RESULTS
HA children showed higher expression levels of genes regulated by HIF (hypoxia inducible factor) and lower levels of those involved in glycolysis and in the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase kinase 1(PDK1) and HIF prolyl hydroxylase 3 (HPH3) mRNA expressions were lowest in children of CMS fathers at altitude. At sea level the pattern of gene expression in the 3 children's groups was indistinguishable.


CONCLUSIONS
The molecular signatures of children of CMS patients show impaired adaptation to hypoxia. At altitude children of CMS fathers had defective coupling between glycolysis and mitochondria TCA cycle, which may be a key mechanism/biomarker for adult CMS. Early biologic markers of disease susceptibility in Andeans might impact health services and social planning.
Huicho
Luis
L
Departament of Paediatrics, Universidad Nacional Mayor de San Marcos, Universidad Peruana Cayetano Heredia, and Instituto de Salud del Niño, Lima, Peru. lhuicho@gmail.com
Xing
Guoqiang
G
Qualls
Clifford
C
Rivera-Ch
María
M
Gamboa
Jorge L
JL
Verma
Ajay
A
Appenzeller
Otto
O
D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D002952:Citric Acid Cycle / Q000502:physiology; D003430:Cross-Sectional Studies; D049308:Dioxygenases / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006019:Glycolysis / Q000502:physiology; D006400:Hematocrit; D006441:Hemoglobin A / Q000032:analysis; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; C028672:hemoglobin AA; D006441:Hemoglobin A; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017346:Protein Serine-Threonine Kinases